Discovery of a bicyclo[4.3.0]nonane derivative DS88790512 as a potent, selective, and orally bioavailable blocker of transient receptor potential canonical 6 (TRPC6)

Bioorg Med Chem Lett. 2018 Jul 1;28(12):2222-2227. doi: 10.1016/j.bmcl.2018.03.056.

Keisuke Motoyama ¹, Tsutomu Nagata ², Jun Kobayashi ³, Akifumi Nakamura ⁴, Naoki Miyoshi ³, Miho Kazui ⁵, Ken Sakurai ⁶, Tomoko Sakakura ⁶

Affiliations

1 End-Organ Disease Laboratories, Daiichi-Sankyo Co. Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: [email protected].
2 Asubio Pharma Co. Ltd., 6-4-3 Minatojima-minamimachi Chuo-ku, Kobe-shi, Hyogo 650-0047, Japan.
3 End-Organ Disease Laboratories, Daiichi-Sankyo Co. Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
4 Modality Research Laboratories, Daiichi-Sankyo Co. Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
5 Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi-Sankyo Co. Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
6 Medicinal Safety Research Laboratories, Daiichi-Sankyo Co. Ltd., 1-16-13 Kitakasai Edogawa-ku, Tokyo 134-8630, Japan.

PMID: 29752182 DOI: 10.1016/j.bmcl.2018.03.056

Abstract

In this study, we aimed to synthesize a novel blocker of transient receptor potential canonical 6 (TRPC6). The sp² carbon atoms of the aminoindane skeleton of the known inhibitor were replaced with sp³ carbon atoms to increase the molecular complexity, measured by fraction sp³ (Fsp³). The representative compound, a bicyclo[4.3.0]nonane derivative DS88790512, inhibited TRPC6 with an IC₅₀ value of 11 nM. Notably, DS88790512 exhibited excellent selectivity against hERG and hNa_V1.5 channels, and was identified as an orally bioavailable compound.

Keywords

Bicyclic molecule; Fsp(3); Ion channel; Na(V)1.5; hERG.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-112298

DS88790512

TRP Channel Inhibitor

TRP Channel

Cardiovascular Disease

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